There are many situations where it is therapeutically desirable to increase the amount of tear fluid produced by the eye. Dry eye disease is the general term for indications produced by abnormalities of the precorneal tear film characterized by a decrease in tear production or an increase in tear film evaporation, together with the ocular surface disease and symptoms that result. Approximately 38 million Americans are affected with some type of dry eye disorder. Among the indications that are referred to by the general term “dry eye disease” are: keratoconjunctivitis sicca (KCS), age-related dry eye, Stevens-Johnson syndrome, Sjogren's syndrome, ocular cicatrical pemphigoid, blepharitis, corneal injury, infection, Riley-Day syndrome, congenital alacrima, nutritional disorders or deficiencies (including vitamins), pharmacologic side effects, contact lens intolerance, eye stress and glandular and tissue destruction, environmental exposure to smog, smoke, excessively dry air, airborne particulates, autoimmune and other immunodeficient disorders, and comatose patients rendered unable to blink.
Dry eye disease, although seen pathologically during ophthalmic exams as superficial punctate keratopathy (SPK) of the ocular surface epithelium, is largely a symptomatic disease. Chronic dryness leads to pain and irritation that is often debilitating to the subject, preventing the performance of normal daily activities such as reading, driving, etc. Dry eye is most common in postmenopausal women; however, hormone replacement therapy has not been proven to help dry eye signs and symptoms.
Currently, the pharmaceutical treatment of dry eye disease is mostly limited to administration of artificial tears (saline solution), anti-inflammatory agents (cyclosporine, steroids) and secretagogues (diquafosol, 15-HETE, rebamipide). In addition, artificial tears often have contraindications and incompatibility with soft contact lenses (M. Lemp, Cornea 9(1), S48-550 (1990)). The use of phosphodiesterase inhibitors, such as 3-isobutyl-1-methylxanthine (IBMX) to stimulate tear secretion is disclosed in U.S. Pat. No. 4,753,945. The effectiveness of these phosphodiesterase inhibitors has been investigated (J. Gilbard, et al., Arch. Ophthal, 112, 1614-16 (1994) and 109, 672-76 (1991); idem, Inv. Ophthal. Vis. Sci. 31, 1381-88 (1990)). Stimulation of tear secretion by topical application of melanocyte stimulating hormones is described in U.S. Pat. No. 4,868,154. Although these interventions can reduce inflammation and/or reduce SPK associated with dry eye, they have not been proven to significantly reduce the symptoms of dry eye.
U.S. Pat. No. 4,313,931 discloses a method of treating reactions provoked by liberation of histamine or serotonin; bronchial asthma; allergic bronchitis; allergic rhinitis; allergic conjunctivitis; or allergic diathesis in a warm-blooded host, which comprises administering to said host an effective amount of a fused dibenzo imidazolo compound such as epinastine.
U.S. Pat. No. 5,942,503 discloses a method for treating pain such as migraine, Bing-Horton syndrome, tension headache, muscular pain, inflammatory pain or neuralgias, in a patient in need thereof which comprises administering to said patient an analgesia producing amount of epinastine or a pharmaceutically acceptable salt thereof.
U.S. Pat. Publication No. 20040097486 discloses a method of treating vernal keratoconjunctivitis, giant papillary conjunctivitis, atopic keratoconjunctivitis, and allergic conjunctivitis in mammals, which comprises administering a composition comprising 0.01-0.3% of an H1 antagonist and 0.05-1.5% of a safe steroid. Vernal keratoconjunctivitis is an allergic type of conjunctivis, which symptoms include severe ocular itching, and mild stringy, mucous discharge. Vernal keratoconjunctivitis is different from keratoconjunctivitis sicca, which is a dry eye disease. All the above cited U.S. Patents are incorporated herein by reference in their entirety.
Abelson, et al., have reported that epinastine reduces redness and itching associated with allergic conjunctivitis (M. B. Clinical Therapeutics, Vol. 26(1), 35-47, (2004)).
Ousler, et al. (Ann Allergy Asthma Immunol. 93:460-4, (2004)) reported that systemic antihistamines, such as loratadine and cetirizine hydrochloride, induced signs and symptoms associated with ocular dryness, including increased corneal and conjunctival staining, decreased TFBUT, and increased ocular discomfort in healthy individuals.
Dry eye disease is different from allergic conjunctivis; the two diseases have different patient populations. Dry eye symptoms are dryness, photophobia, foreign body sensation and grittiness in the eyes. Dry eye symptoms are different from the main complaint of itching associated with allergy, and are not related to histamine activity or allergic response. Redness of the eyes is not a main sign of dry eye disease. The primary end points for studying allergic conjunctivis are generally ocular itching and conjunctival hyperemia. The primary end points for studying dry eye diseases are corneal staining, tear volume (Schirmer tests), dryness, photophobia, foreign body sensation and grittiness.
As a result of the ineffectiveness and inconvenience of current therapies of dry eyes, there remains a need to provide a method for the treatment of dry eye disease, which is not only effective, but also free of significant side effects.